Human studies demonstrate that cancer is largely a preventable disease and that 35-40% of cancer incidence and mortality worldwide can be substantially reduced by changes in the human diet. Specifically, there is compelling worldwide evidence of an association between fruit and vegetable consumption and cancer risk reduction. Other human and animal diseases, as well, are influenced by diet and can be substantially reduced by changes in diet. Examples include diabetes (especially type II diabetes), cardiovascular diseases, Alzheimers disease, osteoporosis, and many others. Likewise, other physical conditions that involve bodily attributes or performance issues, other than diseases, may be affected by diet. The present invention relates to nutrient formulations useful in reducing (including preventing, delaying, inhibiting and/or treating) cancers and other human and animal (especially mammalian) diseases and physical conditions, methods of using such formulations, and methods of identifying such formulations and the components (particularly nutrient ingredients) to be included in the formulations to achieve optimal disease reduction.
As one disease example, tumor development in cancers (carcinogenesis) proceeds through a series of multiple overlapping stages, including initiation (change in DNA), promotion (proliferation of cells with damaged DNA) and progression (growth of cells with cumulative genetic changes, including changes in key control genes that lead to malignant cells and to the emergence of a clinically detectable cancer). Since cancer development may take from 10-30 years, a preferred cancer risk reduction strategy is to insure optimum cellular and tissue health and to minimize cellular events involved in the tumor development process in healthy individuals (typically including those of ages 20-44 or younger) during the early phases of potential or actual carcinogenesis. In one aspect of the invention, this is achieved by the preferably regular, systematic and long-term administration of one or more formulations having multiple active components that, in combination, provide focused antioxidant protection and oxidative balance in the subject. These antioxidant/oxidative balance formulations of the invention provide a particularly useful approach in reducing the risk of cancer diseases generally. In another aspect of the invention, the nutrient formulation contains nutrient components specifically identified and selected to reduce or interfere with a particular disease or disease etiology (such that of a specific cancer disease, e.g. colorectal cancer as discussed below). The invention provides a method of screening and identifying useful components for such formulations. In still another aspect of the invention, the formulations, and the method of screening their components, are directed to the reduction of multiple individual diseases.
Additional protection against disease is required with age (e.g., 45-65, and over 65 years of age) and customized doses of the nutrient formulations of the invention will typically be recommended for high-risk populations (e.g., smokers, genetic risk, cancer survivors, etc.). In the case of cancer, many of these individuals will already have initiated cells, but both promotion and progression are targets for control according to the invention. Accordingly, the nutrient formulations (and their dosage components) are designed specifically for each of the various age groups and relative risk populations.
A comparison of regional human diets with worldwide patterns of cancer incidence strongly suggests that food and nutrition affect cancer incidence and mortality, and therefore cancer risk. Epidemiologic and ecologic evidence indicates that cancer incidence varies significantly between different regions and populations around the world. The observation that the patterns of cancer are sensitive to human migration and urbanization, and the lack of simple patterns of genetic inheritance for most human cancers, indicate that cancer rates are strongly influenced by environmental factors, especially diet. Individual-level epidemiological studies (particularly cohort and case-control studies) provide specific evidence for the identity of some of the dietary patterns and food that may alter risk. Thus, data support the hypothesis that cancer is largely a preventable disease and that the incidence of cancer can be substantially reduced by modifying dietary intake.
The results of a recent report commissioned by the executive officers of the World Cancer Research Fund and the American Institute for Cancer Research estimated that 30-40% of cancer cases throughout the world are preventable by modifications of diet and nutrition [1]. (The references cited herein by reference numeral are listed in the Appendix to this specification.) There is strong and consistent evidence of an association between fruit and vegetable consumption and cancer risk reduction on a worldwide basis [1-4]. In addition, low fruit and vegetable intake is associated with 1.5 to 2 times greater risk of cancer at many sites compared with high intake. Recent reviews have evaluated the large body of evidence concerning the relationship between fruit and vegetable intake and cancer incidence [5-9]. For all cancer sites, a statistically significant protective effect of fruit and vegetable consumption is found in 128 of the 156 dietary studies [3]. The evidence is strongest for lung cancer [5, 8]. In addition, fruit and vegetable consumption is associated with decreased risk for cancers of the pancreas, breast, stomach, colorectal, bladder, cervix, ovaries and endometrium [3].
Evidence now indicates that several types of cancer develop through the progressive acquisition and accumulation of mutations in multiple genes [10, 11]. Genetic mutations can be initiated via a variety of cellular events that are triggered by environmental factors. For example, genotoxic carcinogens or their metabolites act as mutagens by covalently modifying DNA, resulting in chemical changes in the genetic material. In addition, endogenously formed reactive oxygen species (ROS) and metabolites of nitrogen oxide also contribute to DNA damage.
Experimental studies have shown that tumor development proceeds through a series of multiple overlapping stages [12] defined as initiation (changes in DNA), promotion (expansion of numbers of cells with non-repaired or mis-repaired genes) and progression (growth of cells with accumulated genetic changes, some of which are in key genes that lead to cells that are aggressively malignant). In both experimental animal models and humans, there is a latency period between the original carcinogenic event and the development of a malignant tumor. This latency period may be due to several factors, including the complexity of the multistage tumor development process and/or the host""s range of natural defenses against the carcinogenesis process. This long latency period and the multi-stage tumor development process provide multiple opportunities for intervention to prevent and/or delay the development of malignant tumors (i.e., risk reduction).
Numerous scientific studies offer compelling evidence that formulations of mixtures of individual compounds acting at multiple stages of carcinogenesis are most likely to be optimal for cancer risk reduction. For example, epidemiologic studies have demonstrated that diet diversity or the overall pattern of dietary intake may have a greater impact on cancer risk than any one food [435, 436]. In addition, the administration of multiple agent formulations has been shown in some cases to result in synergistic effects, i.e., increased efficacy and potency over individual components, and generally to be significantly less toxic [13-20].
To take the example of colorectal cancer, the now widely accepted adenoma-to-carcinoma progression for colorectal cancer, originally proposed by Hill [255], provides multiple opportunities for intervention during carcinogenesis and makes this disease an excellent candidate for risk reduction strategies. Multiple molecular events are involved in colon carcinogenesis. Initially, the development of an adenoma requires that a stem cell must undergo a first xe2x80x9chitxe2x80x9d (mutation), giving rise to a replicating population of abnormal cells, increasing the odds for additional xe2x80x9chitsxe2x80x9d and malignancy. Secondary to mucosal damage or as a result of high dietary energy intake, proliferation of abnormal colonic epithelial cells increases the opportunity for mutations to go unrepaired, resulting in the expansion of abnormal clones [256]. Based on these mechanisms, the colorectal cancer risk reduction strategy of the present invention is focused on both protecting cellular DNA from genetic alterations and enhancing endogenous mechanisms for regulating cell proliferation. Other examples of diseases susceptible to risk reduction according to the present invention include Type II diabetes, cardiovascular diseases, Alzheimers disease, osteoporosis, and many others. Likewise, other physical conditions that involve bodily attributes or performance issues, other than diseases, may be beneficially affected using the formulations and methods of the present invention.
In one aspect, the present invention includes a bidirectional, three-tiered screening process, which the inventors term xe2x80x9cOrdered Research Information on Nutrientsxe2x80x9d (ORION), to identify and evaluate active components (i.e. nutrient ingredients) for use in the nutrient formulations of the invention. In the first tier of the screening process, ecologic and/or individual-based epidemiological data are examined to establish the patterns of association between diet and foods and disease. The disease under consideration may be a single specific disease, such as a particular form of cancer (e.g. colorectal cancer), or it may be a generalized disease class such as cancer diseases in general. Likewise, the disease under consideration may be a set of one or more specific diseases to be addressed in combination, such as colorectal cancer and lung cancer in combination, or lung cancer and a heart disease in combination. In the second screening tier, the principal (and preferably all) potentially active components from candidate foods and diets that may be implicated in delaying the onset of, or preventing or otherwise inhibiting, the disease (or the set or class of disease) in question are identified. In the third tier, data from studies on the active components are examined to determine their most likely mechanism(s) of action in the multiple pathways identified as important in potentially blocking some specific aspect of the disease process, for example the multi-phased carcinogenesis process. This process may driven from either and/or both directions, i.e., epidemiologic data may drive the process as summarized, or mechanistic evidence may be sufficiently compelling to move upwards to identify the active food ingredients in the target diet.
Because a plurality of active components will be identified as candidates for inclusion in the formulations of the invention, the chemical, pharmacological and toxicological interactions among such components (whether positive, negative or neutral in terms of ultimate therapeutic benefit), are resolved in arriving at the active components to be used in the final formulations of the invention. In addition, the candidate components for a particular disease under consideration may have therapeutically positive or negative cross-over effect(s) with respect to some other disease state. Such cross-over effects are likewise resolved in arriving at the active components to be used in the final formulations of the invention. In this manner, the screening method of the invention leads in a systematic fashion to nutrient formulations having a set of nutrient ingredients, contained in appropriate dosage amounts, that is optimally efficacious with respect to the individual disease or the entire disease set or disease class under consideration, while avoiding negative interactions and cross-over effects among different components and disease states.
Thus, the screening process of the invention utilizes evidence from the three tiers, optimizing the synergy and effectiveness of individual dietary supplements to maximize their integrated disease risk reduction potential in normal and high-risk populations. In selecting key ingredients for the formulations, mixtures of ingredients from target diets and/or mechanistic studies are chosen so as to maximize the synergistic effects, while avoiding or eliminating negative effects, across the spectrum of the disease (e.g. carcinogenesis) pathway(s), and physiologically relevant dosage levels for xe2x80x9cnormalxe2x80x9d populations and more aggressive dosage levels for older and higher risk populations are selected. The formulations are preferably orally ingested by subjects, and are taken on a long-term, continuing and regular basis (especially daily or multiple times daily).
In another embodiment of the bidirectional, three-tiered screening process of the invention, a comprehensive analysis of findings from clinical and basic research is conducted in which geographic (preferably worldwide) disease incidence patterns and relevant dietary micronutrients are analyzed, followed by an in-depth evaluation of human dietary patterns associated with disease at specific organ or system site(s). Next, mechanistic studies of the candidate micronutrient in animals, cellular systems, and other xe2x80x9cin vitroxe2x80x9d models are analyzed and results are integrated for design and formulation decisions. The candidate compounds that are identified from this process are then considered relative to their efficacy in reducing the risk of a specific disease (or class or set of diseases) in relevant human studies and relative to factors such as their bioavailability and potential for synergy with other components. Based on such analysis and identification, final nutrient formulations are designed which optimize desired cellular protection and health synergies and product safety. In a related method, physical conditions influenced by elements of diet other than disease per se are considered according to the foregoing method, so as to screen for active components having:a beneficial effect on, for example, sports performance, beauty and cosmetic appearance, etc.
Still more particularly, the foregoing method may integrate global epidemiological and micronutrient data on cancer incidence and diet with a mechanistic understanding of human carcinogenesis to design organ-specific formulations for cancer risk reduction. Maximization of the synergistic effects of unique mixtures of ingredients is performed across all stages of the carcinogenesis process to optimize dosages based on risks. The method is employed to synthesize evidence from molecular and human epidemiologic studies to create a disease framework that describes the interplay between the molecular mechanisms and exogenous factors, including diet, that impact the carcinogenic process. Evaluation of the scientific literature within this framework results in the creation of an idealized chemoprevention list that includes a large collection of candidate risk reduction compounds that have demonstrated activity throughout the carcinogenic process. The candidate compound list is optimized for risk reduction at specific organ sites by evaluating both the carcinogenic processes unique to a given organ site and the bioavailability of a specific compound for that tissue type. The final product formulation is based on systematic evaluation of the scientific evidence for risk reduction in human populations.
In a related process of the invention, product design and development follows an iterated process that is divided into four rounds of development. In the first round of development, general knowledge regarding the regional distribution of cancer incidence, the unique diets or dietary patterns associated with regions of high and low incidence and the cellular mechanisms involved in disease development are reviewed. A list of candidate compounds for consideration generated. The next stage of product development focuses on a preliminary literature review to summarize current information and hypotheses regarding the development of organ specific cancers including disease etiology, detection, treatment and chemoprevention. A list of candidate compounds for the product formulation is thereby generated. In the third stage of product development, human, animal and in vitro data is evaluated for evidence of efficacy as chemopreventive agents. These investigations focus on mechanism of action, toxicity, safety, bioavailability, opportunities for synergy, formulation and dosage recommendations. The final product formulation is thereby established. In the final stage of product design, specific manufacturing specifications for the final product are ascertained.
In one preferred aspect of the invention, the formulation of the invention is a combination of nutrients useful in maintaining oxidative balance in a human or other mammalian subject, as described in more detail below. This formulation has balanced antioxidant properties and is particularly useful in reducing the risk of cancer diseases generally (i.e., as a disease class). Such a combination preferably comprises the nutrient ingredients specified below, wherein each nutrient ingredient is contained in a measured amount such that the proportional amount of each respective nutrient ingredient, relative to the other nutrient ingredient measured amounts in the combination, is as follows:
Vitamin E: 50-500 IU
Vitamin C: 60-500 mg
Selenium: 20-300 mcg
N-acetyl-l-cysteine: 500-2000 mg
Curcumin: 5-50 mg
Mixed Polyphenols: 500-1500 mg green tea extract, standardized to xe2x89xa760% polyphenols
Mixed Carotenoids: 500-2000 mg mixed vegetable extract, 1200 mg extract being equivalent in mixed carotenoid content to five vegetable servings.
Thus, in this preferred formulation the listed nutrient ingredient components are contained in the combination in relative amounts or ratios defined by the respective content ranges listed. It will be recognized that the absolute concentrations of the listed components may vary among different formulations of the combination, as for example between a dilute formulation and a more concentrated formulation, but the ratios (relative amounts) of the components will nevertheless remain as specified above.
As with other formulations and combinations of the present invention, some or all of the nutrient combination may be formulated in a unit dosage form, such as a pill, capsule or tablet form, or some or all of the combination may be in bulk form such as a powder or liquid (solution, suspension, emulsion, tincture, etc.) form. Preferably, the combination is formulated in a single unit dosage form (e.g. a pill), such that the subject can ingest one or more pills all of the same type according to the recommended administration schedule. Alternatively, depending on exigencies of formulation that are within the skill of the art given the present disclosure, the combination may be formulated in two or more discrete administration forms, preferably packaged together with instructions for use, that together constitute the described combination. For example, the combination may comprise two discrete unit dosage forms (e.g. a pill containing certain of the listed nutrient ingredient components and a capsule containing the remaining components; or a pill containing certain of the listed components and a liquid form containing the rest).
In a particularly preferred form of this oxidative balance formulation, the combination of nutrient ingredients is formulated in such a manner so as to allow the subject to receive daily dosages of the components in approximately the following amounts:
Vitamin E: 400 IU daily
Vitamin C: 500 mg daily
Selenium: 100 mcg daily
N-acetyl-l-cysteine: 1600 mg daily
Curcumin: 10 mg daily
Mixed Polyphenols: 1000 mg daily of green tea extract, standardized to xe2x89xa760% polyphenols
Mixed Carotenoids: 1200 mg daily of mixed vegetable extract equivalent in mixed carotenoid content to five vegetable servings.
It is preferred that the daily dosages of the specified components be within about xc2x120% of the amounts specified above, and more preferably within about xc2x110% of the amounts specified above. Such tolerance ranges for each of the separate components may be specified individually and need not all be the same.
With the exception of the two extract ingredients noted above, the masses specified in the right-hand column correspond to the masses of the specific components listed in the left-hand columns. In the case of selenium, for example, the specified dosage amount is approximately 100 mcg of the element selenium per se; this amount may be incorporated into the formulation in the form of (for example) l-selenomethonine which, of course, will weigh more than 100 mcg.
In this and other formulations of the invention, the components of the combination are preferably packaged together with instructions directing how the combination should be administered to the subject, including for example a timing schedule for administering the combination (e.g, the number of pills to be taken, the number of times each day they should be taken, etc.). Such instructions may also include information identifying the benefits and purposes of the formulation, indications for use, etc.
The above formulation and others of the invention may additionally include other active agents. For example, the formulation above may include one or more additional antioxidant agents beyond the antioxidant active components specified above. In another preferred embodiment, however, the active agents of the formulations (or more specifically, for example, the antioxidant active agents) will consist essentially of those specified in the present disclosure.
In another preferred aspect of the invention, the formulation of the invention is combination of nutrients useful in reducing colorectal cancer risk in a human or other mammalian subject, as described in more detail below. Such a combination preferably comprises the nutrient ingredients specified below, wherein each nutrient ingredient is contained in a measured amount such that the proportional amount of each-respective nutrient ingredient, relative to the other nutrient ingredient measured amounts in the combination, is as follows:
Salicin: 20-200 mg
Curcumin: 5-50 mg
Calcium: 200-2500 mg
Vitamin D: 100-1000 IU
Folic Acid: 200-1000 mcg
Vitamin B6: 0.5-10 mg
Vitamin B12: 0.1-100 mcg.
In a particularly preferred form of this colorectal health formulation, the combination of nutrient ingredients is formulated in such a manner so as to allow the subject to receive daily dosages of the components in approximately the following amounts:
Salicin: 120 mg daily
Curcumin: 10 mg daily
Calcium: 800 mg daily
Vitamin D: 400 IU daily
Folic Acid: 800 mcg daily
Vitamin B6: 2 mg daily
Vitamin B12: 6 mcg daily.
It is preferred that the daily dosages of the specified components be within about xc2x120% of the amounts specified above, and more preferably within about xc2x110% of the amounts specified above. Such tolerance ranges for each of the separate components may be specified individually and need not all be the same.
Other general aspects of this colorectal health formulation, as for example relative vs. absolute amounts of components and the quantitation thereof, the use of unit dosage and/or bulk forms, packaging and providing instructions for use, inclusion of additional active agents, etc., are as summarized above with respect to the oxidative balance nutrient formulation of the invention.
In still another aspect, the invention provides methods of reducing cancer risk generally, and methods of reducing colorectal cancer risk, comprising administering to a human or other mammalian subject a combination of nutrients as specified herein, preferably according to specified administration schedule.
Other aspects of the invention will become apparent from the detailed description below, and from the appended claims.